Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

Lamborn, Ian T.; Jing, Huie; Zhang, Yu; Drutman, Scott B.; Abbott, Jordan K.; Munir, Shirin; Bade, Sangeeta; Murdock, Heardley M.; Santos, Celia P.; Brock, Linda G.; Masutani, Evan; Fordjour, Emmanuel Y.; McElwee, Joshua J.; Hughes, Jason D.; Nichols, Dave P.; Belkadi, Aziz; Oler, Andrew J.; Happel, Corinne S.; Matthews, Helen F.; Abel, Laurent; Collins, Peter L.; Subbarao, Kanta; Gelfand, Erwin W.; Ciancanelli, Michael J.; Casanova, Jean-Laurent; Su, Helen C.

Although RIG-I is thought to function as the major sensor for the orthomyxoviruses and paramyxoviruses especially in mice, a few studies have suggested a role also for MDA5 in responding to influenza A/B viruses and RSV (Sirén et al., 2006; Loo et al., 2008; Grandvaux et al., 2014; Kim et al., 2014; Benitez et al., 2015) . We investigated these possibilities, as the patient had been hospitalized for severe influenza (influenza B in 2011 and influenza A H3N2 in 2011 and 2014) virus was also unaltered in SV40-transformed fibroblasts in which CRI SPR/Cas9 genome editing had been used to generate single-cell clones either hemizygous for the patient's mutant IFIH1 allele or completely lacking both IFIH1 alleles, in contrast to the increased virus production in cells lacking STAT1 (Fig. 8 B and not depicted). The infected cells that were either hemizygous for the patient's mutant IFIH1 allele or completely lacking both IFIH1 alleles did not exhibit increased cytotoxicity or decreased IFN-β production (Fig. 8, C and D) . Finally, using a recombinant RSV that expresses enhanced GFP as a marker of virus replication, we observed that silencing MDA5 did not increase RSV transcripts, although it did decrease IFN-regulated transcripts, especially at 6 h, which were more rapidly induced to higher levels than during HRV infection (Fig. 9 , A-D). Unlike HRV, RSV transcripts or infectivity and spread were not increased in primary respiratory nasal epithelial cells from the patient (Fig. 9 , E and F; and Fig. S1 H) . RSV replication was also unaltered in gene-edited fibroblasts either hemizygous for the patient's mutant IFIH1 allele or completely lacking both IFIH1 alleles (unpublished data). Together, these results show that under the same conditions where MDA5 deficiency results in increased HRV replication, influenza virus and RSV replication remain unaffected. Hence, MDA5 has a nonredundant role in innate and/or cell-intrinsic immunity against respiratory infections caused by HRV.